Dark financial outlook for CIRM

Dark Financial Outlook for CIRM Disclosed Tonight by David Jensen, California Stem Cell Report, January 29, 2009. Excerpts:

The financial condition of California's $3 billion stem cell agency tonight appeared bleak and "daunting," based on briefings provided to its 29-member board of directors.

.....

CIRM's financial plight is the result of California's inability to sell state bonds because of the state's $40 billion budget crisis. CIRM relies on bond sales for funding. It has approved $635 million in grants, many covering several years, but currently does not have the cash to fund all of them.

.....

The briefings disclosed that even if the state budget crisis were solved tomorrow, CIRM would face financial difficulties. That's because it takes time to bring bonds to market. Bonds supporting more critical needs would be sold well before the state would consider offering the CIRM bonds.

Nothing for Genome Canada

Budget 2009: A very dark day for big science by Dale Kirby, Macleans OnCampus, January 29, 2009. News item about an article: Budget erases funding for key science agency by Carolyn Abraham, The Globe and Mail, January 29, 2009. Excerpts from the article:

For the first time in nine years, Genome Canada, a non-profit non-governmental funding organization, was not mentioned in the federal budget and saw its annual cash injection from Ottawa - $140-million last year - disappear.

"We got nothing, nothing, and we don't know why," said a stunned Martin Godbout, Genome Canada president and CEO. "We're devastated."

The news spread like a virus through the research community yesterday as the country's top scientists wondered whether the oversight was a mistake. ...

Genome Canada is a pivotal member of the Cancer Stem Cell Consortium (CSCC).

CIRM videos on YouTube

There's an Announcement, dated January 20, 2009, on the home page of the California Institute for Regenerative Medicine (CIRM), entitled: CIRMTV: CIRM videos now available on YouTube. The link leads to a Playlist of CIRM Video Stem Cell Basics. One of these, Therapies Based on Cancer Stem Cells (4:33 min), features Catriona Jamieson. It currently has a 5-star rating.

For an example of a news release about the work of her group, dated April 7, 2008, see: From Bench to Bedside in One Year: Stem Cell Research Leads to Potential New Therapy for Rare Blood Disorder by Debra Kain, University of California - San Diego News Center. The first sentence:

A unique partnership between industry and academia has led to human clinical trials of a new drug for a rare class of blood diseases called myeloproliferative disorders (MPD), which are all driven by the same genetic mutation and can evolve into leukemia.

This research was funded in part by a grant from CIRM.

Two reports about perpetuation of leukaemias

1) Hedgehog blocker thwarts cancer stem cells, ecancermedicalscience Insider News, January 25, 2009. Excerpt:

The hedgehog signalling pathway helps to maintain leukaemia stem cells, which are the very cells that spread the disease, Tannishtha Reya and colleagues report. When a small inhibitory molecule is used to disrupt the pathway in a mouse model, the cancer stem cells become depleted.

The publication referred to is: Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia by Chen Zhao and 13 co-authors, including Catriona H Jamieson and Tannishtha Reya, Nature 2009(Jan 25) [Epub ahead of print][PubMed Citation].

Added February 10, 2009: Self-renewing blood and leukaemia cells need hedgehog by Simone Alves, Nature Reports Stem Cells, February 5, 2009.

Added February 24, 2009: Cancer stem cells: Killing hedgehog to treat CML by Emily J Chenette, Nature Reviews Cancer 2009(Mar); 9: 148-9.

2) Stalling cell division keeps leukaemia stem cells going by Monya Baker, Nature Reports Stem Cells, January 8, 2009. [The full text is publicly accessible]. The first paragraph:

To sustain disease, leukemia stem cells have to keep on dividing. To do so cells require a counterintuitive resource: a protein that keeps cells from proliferating. Work reported in Nature this month shows that, by giving cancer stem cells a chance to slow down and repair DNA damage, the protein p21, a cell-cycle inhibitor, not only helps cancer maintain itself, it helps leukemia evade therapies designed to kill rapidly dividing cells. Drugs that inhibit p21 or DNA repair, then, might help leukemia speed up and self destruct.

The publication referred to is: Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells by Andrea Viale and 13 co-authors, including Pier Giuseppe Pelicci, Nature 2009(Jan 1); 457(7225): 51-6 [PubMed Citation].

Added February 10, 2009: Regulation of leukemic stem cells self-renewal and quiescence - the role of p21 by Lei Ying, Hematopoiesis, February 8, 2009.

Neoplastic transformation of intestinal SC

Cancer stem cells: Can mutated stem cells produce tumours? by Nicola McCarthy, Nat Rev Cancer 2009(Feb); 9(2): 74 [full text accessible after free registration]. Last sentence:

Both papers indicate that a single mutation in normal intestinal stem cells can give rise to tumours, as has been suggested. It is interesting that, although LGR5 and PROM1 seem to mark similar stem cells in the small intestine, PROM1 does not mark colonic stem cells, whereas LGR5 does. This illustrates the need to clearly define markers and their limitations if we are to begin to understand the contribution of normal tissue stem cells and cancer stem cells to tumorigenesis.

The two papers referred to are these [neither are publicly accessible]:

1) Crypt stem cells as the cells-of-origin of intestinal cancer by Nick Barker and 9 co-authors, including Hans Clevers, Nature 2008(Dec 17) [Epub ahead of print][PubMed Citation].

2) Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation by Liqin Zhu and 9 co-authors, including Richard Gilbertson, Nature 2008(Dec 17) [Epub ahead of print][PubMed Citation].

See also this blog post: Two articles linking normal intestinal SC to CSC, December 18, 2008.

Targeting tumorogenic cells in neuroblastoma cell lines

Neuroblastoma Cell Lines Contain Pluripotent Tumor Initiating Cells That Are Susceptible to a Targeted Oncolytic Virus by Yonatan Y Mahller and 8 co-authors, including Timothy P Cripe, PLoS ONE 2009; 4(1): e4235 [Epub 2009 Jan 21]. [The full text is openly accessible]. PubMed Abstract:

BACKGROUND: Although disease remission can frequently be achieved for patients with neuroblastoma, relapse is common. The cancer stem cell theory suggests that rare tumorigenic cells, resistant to conventional therapy, are responsible for relapse. If true for neuroblastoma, improved cure rates may only be achieved via identification and therapeutic targeting of the neuroblastoma tumor initiating cell. Based on cues from normal stem cells, evidence for tumor populating progenitor cells has been found in a variety of cancers. METHODOLOGY/PRINCIPAL FINDINGS: Four of eight human neuroblastoma cell lines formed tumorspheres in neural stem cell media, and all contained some cells that expressed neurogenic stem cell markers including CD133, ABCG2, and nestin. Three lines tested could be induced into multi-lineage differentiation. LA-N-5 spheres were further studied and showed a verapamil-sensitive side population, relative resistance to doxorubicin, and CD133+ cells showed increased sphere formation and tumorigenicity. Oncolytic viruses, engineered to be clinically safe by genetic mutation, are emerging as next generation anticancer therapeutics. Because oncolytic viruses circumvent typical drug-resistance mechanisms, they may represent an effective therapy for chemotherapy-resistant tumor initiating cells. A Nestin-targeted oncolytic herpes simplex virus efficiently replicated within and killed neuroblastoma tumor initiating cells preventing their ability to form tumors in athymic nude mice. CONCLUSIONS/SIGNIFICANCE: These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus.

Examples of news items about this publication:

Targeting Cancer's Own Stem Cells to Fight Recurrence, Forbes, January 21, 2009. First paragraph:

Scientists have located a group of cancer stem cells or "tumor-initiating cells" which, when targeted with a reprogrammed herpes virus, are prevented from turning malignant.

Engineered Virus Targets And Kills Apparent Cancer Stem Cells In Neuroblastoma, ScienceDaily, January 21, 2009. First paragraph:

After identifying an apparent population of cancer stem cells for neuroblastoma, researchers successfully used a reprogrammed herpes virus to block tumor formation in mice by targeting and killing the cells.

Virus made to kill cancer stem cells, UPI, January 22, 2009. First paragraph:

U.S. scientists say they have engineered a virus to target and kill apparent cancer stem cells involved in neuroblastoma tumors.

More on first CCSIP Call for Proposals

The First CCSIP Call for Proposals was blogged on January 6, 2009.

A link to LOI Instructions has now been added to the Programs and Activities page of the website of the Canada-California Strategic Innovation Partnership (CCSIP). The PDF that's provided is entitled: Canada-California Strategic Innovation Partnership (CCSIP): Letter of Intent (LOI) Submission Instructions. Excerpt:

Letters of Intent must be submitted by Friday, February 27, 2009 before 2 p.m. Pacific Time/ 5 p.m. Eastern Time. We encourage early submission of LOIs. Please note: LOIs will not be accepted after the deadline.

SC markers invention

United States Patent Application 20090012024, Anne Collins, Norman Maitland, Steven Bryce, January 8, 2009. [See also: Stem Cell Markers and Stem cell markers]. Abstract:

We disclose gene markers of stem cells, typically prostate stem cells, and in particular cancer stem cells, for example prostate cancer stem cells; therapeutic agents and diagnostic assays based on said stem cell genes; and including screening assays to identify therapeutic agents.

Excerpt:

[0030]We have conducted gene array analysis to identify genes that are characteristic of cancer stem cells which show an up regulation when compared to control stem cell samples from normal or benign stem cell populations. We herein disclose these genes and their use in the identification of therapeutic agents useful in the treatment of cancer, in particular prostate cancer, and in the development of diagnostic assays for the detection of the early on set of tumour cell growth. The present disclosure relates to the identification of cancer stem cell specific genes.

An earlier Patent Application: 20080233640, Norman James Maitland, Anne Collins, September 25, 2008. [See also: Prostate Stem Cell and Prostate stem cell]. Abstract:

We describe a method for the isolation of prostate stem cells, typically prostate stem cells which express CD 133 antigen; stem cells and cancer stem cells isolated by the method and their use.

Two recent publications from this research group [not publicly accessible]:

Inflammation as the primary aetiological agent of human prostate cancer: a stem cell connection? Norman J Maitland, Anne T Collins, J Cell Biochem 2008(Nov 1); 105(4): 931-9 [PubMed Citation].

Prostate cancer stem cells: a new target for therapy, Norman J Maitland, Anne T Collins, J Clin Oncol 2008(Jun 10); 26(17): 2862-70 [PubMed Citation].

A recent news item:

Investors back their belief in biotech company by Bernard Ginns, Yorkshire Post, January 20, 2009. Excerpts:

Pro-Cure's expertise is in the culture, isolation, handling and gene profiling of human prostate cancer stem cells. It is working with a number of big pharmaceutical firms in this burgeoning area.

Its management team includes Professor Norman Maitland, director of Yorkshire Cancer Research and professor of molecular biology at the University of York, who is regarded as one of the world leaders in his field.

The website for Pro-Cure Therapeutics includes a page about the Management Team.

Multidrug resistance and CSCs

Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities by Macus Tien Kuo, Antioxid Redox Signal 2009(Jan); 11(1): 99–134 [PubMed Citation]. Examples of sections of this review, accessible via the Author Manuscript in PMC:

IX. Redox Signaling in Multidrug-Resistant Cancer Stem Cells. Excerpt:

C. Signaling pathways in cancer stem cells

In addition to the efflux multidrug transporters, several crucial signaling pathways have been elucidated for cancer stem cell biology, including Wnt/β-catenin, Notch, sonic hedgehog, Bmi-1, the Hox family, and PTEN (161). Here, only the pathways that are most relevant to multidrug resistance are discussed.

X. Therapeutic Opportunities for Cancer Stem Cells. Final paragraph of this section:

Because cancer stem cells share many common features with those found in normal stem cells, caution must be exercised to avoid harming the normal stem cells (such as those in the bone marrow) during treatment. As better understanding of the role of cancer stem cells in the evolution of drug resistance is reached, one can expect that better treatment modalities targeting cancer stem cells also will be developed.

[The Author Manuscript in PMC is publicly accessible].

Comparing SC from the adult human brain and from brain tumors

A comparison between stem cells from the adult human brain and from brain tumors by Mercy Varghese and 8 co-authors, including Iver A Langmoen, Neurosurgery 2008(Dec); 63(6): 1022-34 [PubMed Citation].

Evaluation: Tali Siegal: Faculty of 1000 Medicine, 6 Jan 2009. Excerpt:

This study provides further evidence in support of the theory of human brain tumors deriving from apparent stem cell populations, rather than from transformation and differentiation of glial cells. The implication is that glioma stem cells should become the targets of future therapies, and, to that end, understanding the differences between normal and abnormally derived cells is important.

Support for Warburg theory of cancer

Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer by Michael A Kiebish, Xianlin Han, Hua Cheng, Jeffrey H Chuang and Thomas N Seyfried, J Lipid Res 2008(Dec); 49(12): 2545-56 [Epub 2008 Aug 13][PubMed Citation]. News items:

Study results from Boston College, Department of Biology in the area of brain cancer cell biology published, Pharmacy Choice, December 29, 2008.

Don't Throw Off Warburg Theory of Cancer Just Yet, Medgadget, January 12, 2009. Excerpt:

Boston College biologists and colleagues at Washington University School of Medicine found new evidence to support Warburg's theory by examining mitochondrial lipids in a diverse group of mouse brain tumors, specifically a complex lipid known as cardiolipin (CL). They reported their findings in the December edition of the Journal of Lipid Research.

Characterization of human ESC with features of neoplastic progression

Characterization of human embryonic stem cells with features of neoplastic progression by Tamra E Werbowetski-Ogilvie and 15 co-authors, including Mickie Bhatia, Nat Biotechnol 2009(Jan 4) [Epub ahead of print][PubMed Citation]. Examples of news items about this research:

Scientists can now differentiate between healthy cells and cancer cells, Daily News, McMaster University, January 5, 2009.

Canadian researchers discover how to ID 'bad' from normal stem cells, CBC News, January 5, 2008.

Tests helps tease out 'good' stem cells from cancer-causing ones: study by Sheryl Ubelacker, The Canadian Press, 2009. The first two sentences:

One of the big worries about one day using stem cells to grow new organs and other tissues for curing disease is that these little regenerative powerhouses could give rise to tumours and end up doing more harm than good.

Now Canadian researchers have found a way to tell good stem cells from bad.

Minireview: PTEN, SC , and CSC

PTEN, stem cells, and cancer stem cells by Reginald Hill and Hong Wu, J Biol Chem 2008(Dec 30) [Epub ahead of print]. [Accepted Manuscript] PubMed Abstract:

Like normal stem cells, "cancer stem cells" (CSCs) have the capacity for indefinite proliferation and generation of new cancerous tissues through self-renewal and differentiation. Among the major intracellular signaling pathways, Wnt, Shh, and Notch are known to be important in regulating normal stem cell activities and their alterations are associated with tumorigenesis. It has become clear recently that phosphatase and tensin homologue (PTEN) is also critical for stem cell maintenance and that PTEN loss can cause the development of CSCs and ultimately tumorigenesis.

Autophagy and tumor dormancy in human ovarian cancer cells

The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells by Zhen Lu and 11 co-authors, including Robert C. Bast, Jr., J Clin Invest 2008(Dec 1); 118(12): 3917-29. [PubMed Citation]. The last sentence of the Abstract:

Thus, ARHI can induce autophagic cell death, but can also promote tumor dormancy in the presence of factors that promote survival in the cancer microenvironment.

A Commentary: Autophagy-induced tumor dormancy in ovarian cancer by Ravi K Amaravadi, J Clin Invest 2008(Dec 1); 118(12): 3837-40. PubMed Abstract:

Autophagy--a process of "self-eating" that involves enzymatic digestion and recycling of cellular constituents in response to stress--contributes to both cancer cell death and survival. In this issue of the JCI, Lu et al. report that controlled induction of tumor suppressor gene aplasia Ras homolog member I (ARHI) results in autophagic cell death of human ovarian cancer cells in vitro (see the related article beginning on page 3917). However, within xenograft tumors in mice, multiple factors within the tumor microenvironment switched ARHI-induced autophagy to a mechanism of tumor cell survival, leading to tumor dormancy. Since ARHI expression is suppressed in the majority of breast and ovarian cancers but is high in premalignant lesions, ARHI-induced autophagy could be manipulated for therapeutic benefit.

[The JCI publishes all research articles immediately in PubMed Central].

See also: Dormant Cancer Cells Rely on Cellular Self-Cannibalization to Survive, News Release, The University of Texas M. D. Anderson Cancer Center, December 31, 2008.

First CCSIP Call for Proposals

The Canada-California Strategic Innovation Partnership (CCSIP) has announced, in its News and Publications section, its first Call for Proposals (CFP) for Collaborative Initiatives Between California and Canada [16-page PDF], dated December 23, 2008. A Promotional Summary [3-page PDF] and FAQ Document [5-page PDF] are also available. The 16-page CFP is also available via the websites of ISTPCanada and the University of California Office of the President. An excerpt from the FAQ:

2. What types of proposals are requested under this CFP?

CCSIP is hosting a university-led Call for Proposals for Collaborative Initiatives between Canada and California. The objective of this CFP is to stimulate novel ideas, and catalyze the development of innovative multi–campus and multi–disciplinary research and educational collaborations between the two jurisdictions.

Under this CCSIP CFP, financial support is available for two types of bilateral initiatives, including the:

• Conduct of focused bilateral round tables, workshops and/or symposia that lead to novel methods or approaches for collaborative research. These proposals should request $15,000 to $50,000 in total funding².

[Footnote 2: Includes funds from both Canadian and Californian sponsors]

• Development and delivery of a detailed R&D business plans for early-stage bilateral initiatives that help to propel the concept to the next stage of development (following the conduct of workshops and associated research). These proposals should request about $100,000 in total funding.

Excerpts from the Promotional Summary:

Eligibility:

Each proposal must include a Principal Investigator (PI) from a participating Canadian university¹, and a PI from the University of California system.

[Footnote 1: A current list of participating Canadian universities may be found in Appendix A of the CFP document]

[Some paragraphs omitted, including a section on Type of Proposals Requested]

Focus of Proposals:

Bilateral university research teams are encouraged to put forward short proposals for collaborative initiatives that aim to address key priorities shared by California and Canada, capitalize on the complementary strengths of both jurisdictions and emphasize delivery to the market place.

[Some paragraphs omitted, including sections on Selection Criteria, Specifications for Letters of Intent and Complete Proposals, and Evaluation Process]

Deadlines:

• Letters of Intent: February 27, 2009; 2PM PST, UCOP and ISTPCanada will announce all selected Letters on March 16, 2009
• Requested Proposals: May 1, 2009, 2PM PST
• Funding Decisions: The CCSIP Steering Committee, together with UCOP and ISTPCanada, expect to announce funding for all successful bilateral initiatives by July 1, 2009

[Some additional paragraphs omitted, including sections on How to Apply and Additional Information]

Note that, in the Areas of Focus section of the CCSIP website, the first topic listed under Specific RD&D Project Areas is: Cancer Stem Cells.

A relevant previous post is: News release from CCISP, December 13, 2008.

Thanks to Cindy Bell for information about the first CCSIP Call for Proposals.